Cardiac complications in patients with COVID-19: a systematic review

Cardiac complications in patients with COVID-19 have been described in the literature with an important impact on outcome. The primary objective of our systematic review was to describe the kind of cardiac complications observed in COVID-19 patients and to identify potential predictors of cardiovascular events. The secondary aim was to analyze the effect of cardiac complications on outcome. We performed this systematic review according to PRISMA guidelines using several databases for studies evaluating the type of cardiac complications and risk factors in COVID-19 patients. We also calculated the risk ratio (RR) and 95% CI. A random-effects model was applied to analyze the data. The heterogeneity of the retrieved trials was evaluated through the I2 statistic. Our systematic review included 49 studies. Acute cardiac injury was evaluated in 20 articles. Heart failure and cardiogenic shock were reported in 10 articles. Myocardial infarction was evaluated in seven of the papers retrieved. Takotsubo, myocarditis, and pericardial effusion were reported in six, twelve, and five articles, respectively. Arrhythmic complications were evaluated in thirteen studies. Right ventricular dysfunction was evaluated in six articles. We included 7 studies investigating 2115 patients in the meta-analysis. The RR was 0.20 (95% CI: 0.17 to 0.24; P < 0.00001, I2 = 0.75). Acute cardiac injury represented the prevalent cardiac complications observed in COVID-19 patients (from 20 to 45% of the patients). Patients with acute cardiac injury seemed to be significantly older, with comorbidities, more likely to develop complications, and with higher mortality rates. Acute cardiac injury was found to be an independent risk factor for severe forms of SARS-CoV-2 infection and an independent predictor of mortality. Due to the scarce evidence, it was not possible to draw any conclusion regarding Takotsubo, myocarditis, pleural effusion, and right ventricular dysfunction in COVID-19 patients. Noteworthy, possible arrhythmic alterations (incidence rate of arrhythmia from 3 to 60%) in COVID-19 patients have to be taken into account for the possible complications and the consequent hemodynamic instabilities. Hypertension seemed to represent the most common comorbidities in COVID-19 patients (from 30 to 59.8%). The prevalence of cardiovascular disease (CVD) was high in this group of patients (up to 57%), with coronary artery disease in around 10% of the cases. In the majority of the studies retrieved, patients with CVD had a higher prevalence of severe form, ICU admission, and higher mortality rates.


Background
From December 2019, when a new severe respiratory disease was reported in Wuhan, China, the infection caused by a novel coronavirus quickly spread across the globe causing a pandemic with devastating consequences [1] and challenging health care organization [2].
Although COVID-19 is characterized mainly by upper and lower respiratory system involvement, with consequent respiratory symptoms at different grades of severity (from cough to shortness of breath, to dyspnea, to respiratory failure), evidence of extrapulmonary manifestations is established [3][4][5] including venous and arterial thrombotic manifestations [6,7]. Cardiac complications (i.e., acute cardiac injury, cardiogenic shock, heart failure, arrhythmia, right ventricular dysfunction) have been described in the literature with an important impact on outcome [8]. Several mechanisms are implicated in the genesis of cardiac complications in patients with COVID-19: direct myocardial cells injury (through ACE2 receptors), systemic inflammation, catecholamine surge, cytokine storm, electrolyte imbalance, and hypoxia [9]. Consequently, it was extremely important to further report the cardiological events related to COVID-19 and identify possible risk factors (e.g., hypertension, diabetes) in order to stratify patients with increased risk of cardiovascular events during SARS-CoV-2.
The primary objective of our systematic review was to describe the type of cardiac complications in patients with COVID-19 and the potential associated risk factors (i.e., hypertension, diabetes, previous stroke, previous cardiovascular events, respiratory diseases, COPD, malignancy, chronic kidney disease, chronic liver disease) that may allow the identification of patients more exposed to cardiovascular events represented our secondary aim. The secondary aim was to analyze the relation between cardiac complications and outcome.

Protocol and registration
The authors performed this systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statements [10]. PROSPERO registration number: CRD42021231922.

Search
We systematically explored the US National Library of Medicine database (MEDLINE), Web of Science, Google Scholar, Scopus, Cinhal Database, and Cochrane Central Register of Controlled clinical studies (CENTRAL) for RCT, case report, case series, letters to the editor, correspondence, abstracts, and brief reports from 2019 to 2021. We did not impose any restrictions for language. The search criteria were (arrhythmia OR cardiac ischemia OR cardiogenic shock OR acute myocardial infarction OR Heart failure OR Myocarditis OR right ventricle dysfunction) AND (COVID-19 OR coronavirus OR coronavirus pandemic OR coronavirus pneumonia) AND (comorbidities OR hypertension OR Diabetes OR dyslipidemia OR smoker OR chronic obstructive pulmonary disease OR COPD OR chronic kidney disease OR chronic kidney failure OR stroke OR Chronic liver failure OR hyperthyroidism OR dementia). Furthermore, we hand-searched the reference lists of the articles in order to find all relevant articles missed by electronic search. The research was limited to randomized, observational, and retrospective studies, case report, case series, letters to the editor, correspondence, abstracts, and brief reports on human subjects that describe the type of cardiac complications in COVID patients and the possible clinical factors that may allow the identification of patients with a high risk of cardiovascular events.

Eligibility and study selection
We included randomized, case-controlled, and cohort studies (both prospective and retrospective), case report, and case series evaluating the type of cardiac complications in COVID-19 patients and the possible clinical risk factors. Reviews, conference proceedings, meta-analyses, and international expert recommendations were not included. The authors screened all search results, titles, and abstracts of retrieved articles to assess eligibility and then obtained a full-length manuscript for all the included studies. Among the publications identified, we excluded studies of irrelevance to the topic, technical descriptions, proceeding, and non-human model studies.

Data collection
A data collection form was created with the following main study characteristics: authors, year of publication, country, number of patients included, study design, primary outcome, other outcomes, number of treatment/ control, inclusion criteria, exclusion criteria, quality of the evidence, age, sex, cardiological comorbidities, other comorbidities, COVID-19 severity, characteristics of cardiac complication analyzed, other cardiological complications (respiratory, neurological, infections), and outcomes. The authors screened all search results by literature search. One investigator (F.M.) was in charge of collecting the data and assessing the methodological validity of all the eligible studies. Then, all the data were verified by two further investigators (E.B., F.F.).

Outcome
The primary objective was to describe the type of cardiac complications observed in COVID-19 patients and to identify possible clinical risk factors (i.e., hypertension, diabetes, dyslipidemia, smoking, coronary heart disease previous stroke, previous cardiovascular events, respiratory diseases, COPD, malignancy, chronic kidney disease, chronic liver disease) that may allow the identification of patients with a high risk of cardiovascular complications in comparison with patients without risk factors. The secondary aim was to analyze the effects of cardiac complications on mortality.

Assessment of study quality
For randomized studies, the selected articles were evaluated using the 3-item, 5-point Oxford Quality Scale. Studies are rated on the basis of three methodological features: 2 points for descriptions of randomization, 2 points for the description of the blinding process, and 1 point for the description of withdrawal. We excluded from this review all articles which did not obtain a minimum score of 2. The Newcastle-Ottawa Scale was used for case-controlled or cohort studies quality assessment.
Each study is judged on three broad perspectives: the choice of the study groups, the comparability of the groups, and also the ascertainment of either the exposure or the outcome of interest for case-control or cohort studies, respectively.

Strategy for data synthesis
We created a descriptive summary table with the main characteristics of included studies (Table 1). Then, we also created descriptive tables for the following cardiac complications (from Tables 2, 3, 4, 5, and 6; a graphical representation of the cardiac complications is shown in Fig. 1): 1. Acute cardiac injury 2. Acute myocardial infarction 3. Takotsubo syndrome 4. Myocarditis 5. Pericardial effusion 6. Arrhythmias

Right ventricular dysfunction
For all patients who were reported to have cardiovascular complications, we analyzed demographics (age, sex), risk factors/comorbidities, clinical features (cardiac biomarkers, ECG, and/or echocardiographic findings), and their relation with outcome. A major limitation of this review includes the heterogeneity in cardiac injury definition (ECG/biomarkers). The authors of this systematic review reported the definition provided by the authors for each article included.

Statistical analysis
The Cochrane handbook for systematic reviews of interventions [59] and Hozo and coll [60]. recommendations were followed in order to perform the meta-analysis.
Secondary outcome data were extracted only from the published articles retrieved. Publication bias was evaluated by analyzing the funnel plots. We calculated risk ratio (RR) and 95% confidence interval (CI) to summarize continuous data. A random-effects model was applied to analyze the data. The heterogeneity of the retrieved trials was evaluated through the I 2 statistic. I 2 values above 75% reflected a high heterogeneity [61,62]. Subgroup analyses were performed as sensitivity analysis according to the type of cardiac complications (acute cardiac injury, cardiogenic shock, heart failure, arrhythmia, right ventricular dysfunction). All statistical analyses were performed using Review Manager (RevMan; Computer program. Version 5.3 Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012).

Results
Electronic literature searches identified 605 articles, and 16 further citations were found by hand searching the reference lists of the studies. We initially excluded articles as not relevant for the aim of the review basing on the abstract. We selected 78 articles for full-text review. Twenty-nine studies were further excluded for one of the following reasons: outcome was not reported, preliminary studies, and technical descriptions. Our review finally included 49 clinical studies (Fig. 2). Study characteristics and outcomes are listed in Table 1.
The current study was performed between January and September.
In the retrospective study of Kunal et al., the authors enrolled 108 patients with COVID-19 [32] and ACI was defined as serum levels of troponin T above the 99th percentile upper reference limit. The authors found that ACI was the most common CV complication (25.9% of the patients). Heart failure, cardiogenic shock, and acute coronary syndrome were observed in 3.7% of the patients. Patients with ACI were significantly older and had a greater frequency of hypertension, diabetes, and cardiovascular disease in their medical history (P = 0.001). The authors also found a statistically significant difference between non-survivor and survivor in patients with acute cardiac injury (P = 0.01). No correlation was observed regarding the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and acute cardiac injury. Univariate logistic regression analysis found that acute cardiac injury was a predictor of mortality (OR: 6.28; 95% CI: 2.44-16.17; P < 0.0001). Multivariate logistic regression analysis found that acute cardiac injury was the independent predictor of mortality (OR: 11.3; 95% CI: 2.31-55.54; P = 0.003). Likewise, in the retrospective study of Guo et al., the authors found cardiac injury in 27.8% of the COVID-19 patients [25]. Cardiac injury was defined as serum levels of troponin T above the 99th percentile upper reference limit. Patients with cardiac injury had a significantly higher rate of hypertension (P < 0.001), coronary artery disease (P < 0.001), cardiomyopathy (P < 0.001), diabetes (P < 0.001), chronic obstructive pulmonary disease (P = 0.001), and history of ACEI/ARB use (P = 0.002). Patients with cardiac injury were more likely to develop complications during hospital stay (i.e., malignant arrhythmia, acute respiratory distress syndrome, acute coagulopathy acute kidney injury). The mortality rate was 37.50% for patients with cardiac injury and 69.44% for patients with cardiac injury and cardiovascular disease in their medical history. Shi et al., in a retrospective study of 416 patients, evaluated the incidence of cardiac complications and the association between cardiac injury and mortality [43]. Cardiac injury was defined as an increase of troponin above the 99th percentile upper reference limit. A diagnosis of acute cardiac injury was made in 82 patients (19.7%). Patients with ACI were older and with comorbidities (i.e., hypertension, coronary heart disease, cerebrovascular disease, chronic heart failure) in comparison to COVID patients without cardiac injury (P < 0.001). Troponin and pro-BNP levels were statistically significantly higher in patients with cardiac injury (P < 0.001). Even more, in the group of cardiac injury patients, the authors found a higher incidence of invasive mechanical ventilation, use of antibiotics, glucocorticoids, immunoglobulin, acute kidney injury, electrolytes alterations, coagulation disorders, and ARDS. The mortality rate was also higher in this group of patients (P < 0.001). Similar findings can be observed in the singlecenter retrospective observational study by Xiong et al., evaluating the cardiovascular implication in COVID-19 patients [52]. Cardiac injury was defined as an increase in serum troponin T above the upper limit of reference (> 0.02 ng/mL), whereas acute heart failure was defined as the presence of typical symptoms in addition to signs of structural and/or functional cardiac abnormalities. They found that 19.8% had acute cardiac injury and 18.1% had acute heart failure. Acute cardiac injury was the most common complication among COVID-19 patients. The prevalence of cardiac complications was    [17]. They found that cardiac complications were more frequent in non-survivor patients in comparison to recovered patients (association between complications and outcomes). In particular, the authors found that 77% of patients with a diagnosis of acute cardiac injury (defined on the basis of cardiac biomarkers and/or ECG alterations) died; half of these patients presented hypertension or cardiological disease in their medical history. Heart failure (defined on the basis of age-related pro-BNP) was observed in 49% of dead patients: half of these patients presented hypertension or cardiological disease in their medical history. Shi et al., in a retrospective study of 671 patients, evaluated the clinical characteristics and the impact on outcome of cardiac complications in COVID-19 patients [44]. Cardiac injury was defined as an increase of cardiac biomarkers above the 99th percentile upper reference limit. Patients were divided into survivors and non-survivors. The cause of death was attributed to ACI in 30.6% of the patients. Patients with cardiac injury were older and with more comorbidities in comparison to COVID patients without cardiac injury (P < 0.001). Acute heart failure represented the cause of death in 19.4% of the patients. Du et al. retrospectively analyzed the risk factors and clinical features of 85 COVID-19 patients who died [22]. ACI was observed in 44.7% of the patients. Cardiac arrest represented 8.64% of cases of death. Acute coronary syndrome represented 4.94% of cases of death. Similar results were reported in the remaining included studies, with the percentage of acute cardiac injury varied from 12 to 55% [15,27,42,53,54,[56][57][58]. Contrarily, Wan et al. found that acute cardiac injury was observed in 7.4% of the cases; no  statistical difference was found between the percentage of acute cardiac injury in mild and severe forms [50]. The authors examined the clinical feature of COVID-19 patients and divided the enrolled patients into mild and severe forms (respiratory rate > 30 beats/minute, mean oxygen saturation < 93%, PaO 2 /FiO 2 < 300). The prospective international study by Dweck et al. reported data from 1216 echocardiographic examinations in COVID-19 patients [24]. The indications for echocardiographic evaluation were suspected left heart failure in 40%, elevated cardiac biomarkers in 26%, right heart failure in 20%, and ST-segment elevation in 9% of the cases. Chest pain and ST-segment elevation represented the indication for performing echocardiographic evaluation in 13% of the cases (14 patients). Severe impairment of the left ventricle was observed in 9% of the cases (112 patients) and of the right ventricle in 6%. New myocardial infarction was observed in 3% of the population examined [24]. Seven percent of these patients exhibited elevated levels of troponin and/or BNP. Similarly, the prospective study of Szekely et al. aimed to perform a comprehensive echocardiographic evaluation of COVID-19 patients [47]. One hundred patients were enrolled of whom 68% showed echocardiographic abnormalities: RV dilatation (39%), LV diastolic dysfunction (16%), and LV systolic dysfunction (20%). Troponin level above the 99th percentile was reported in 20% of the patients. Comorbidities were observed in 72% of the patients.
The retrospective study by Chen et al., on 54 patients, aimed to evaluate cardiac complications on COVID-19 patients and to identify possible risk factors [16]. Patients were divided into critical and severe forms of COVID-19 based on clinical evaluation (i.e., respiratory rate, peripheral oxygen saturation and gas exchange, respiratory failure, mechanical ventilation requirement, organ dysfunction, shock). An echocardiographic scan was performed in 31 patients: new-onset heart failure was observed in 20% of critically ill patients; 13.3% presented with right heart failure and pulmonary hypertension and 6.7% with left heart failure. Severe cardiac injury was found to be an independent risk factor predicting the critical status of COVID-19 patients (OR = 2.4, 95% CI 1.8-20.1, P = 0.4).
Concerning acute myocardial infarction, in the retrospective study of Stefanini et al., the authors evaluated the incidence, clinical presentation, angiographic findings, and outcome of 28 COVID-19 patients who underwent urgent coronary angiography for STEMI [46]. STEMI was defined according to ESC guidelines [65]. 71.4% of the population had hypertension in their medical history, 32.1% diabetes mellitus, 28.6% chronic kidney disease, and 10.7% previous myocardial infarction. In 85.7% of the cases, STEMI represented the cause of hospitalization. At echocardiographic evaluation, left ventricular ejection fraction < 50% was observed in 60.7% of the cases, 82.1% presented regional wall abnormalities, 10.7% diffuse hypokinesia, and 7.1% no abnormalities. On coronary angiography evaluation, 60.7% presented a culprit lesion needing revascularization, whereas 39.3% did not present coronary artery disease. No one underwent fibrinolysis. A follow-up evaluation reported that 39.3% of patients died, 3.6% were still in hospital, and 57.1% had been discharged. On the same aspect, Bangalore et al. detected 18 COVID-19 patients with ST-segment: in 8 patients, the diagnosis of myocardial infarction was confirmed (i.e., coronary angiography, echocardiography) [13]. The group of patients with myocardial infarction presented a high incidence of hypertension (86%), hypercholesterolemia (29%), and diabetes mellitus (43%) as risk factors. Even more, the echocardiographic evaluation showed a low ejection fraction in 88% of the cases and regional wall motion abnormality in 75% and a higher level of troponin and D-dimer. Six out of eight patients underwent coronary angiography: 5 patients were treated with PCI. In-hospital mortality occurred in 50% of patients with myocardial infarction.
To summarize, patients with acute cardiac injury seemed to be significantly older, with comorbidities, more likely to develop complications, and with higher mortality rates. Acute cardiac injury represented the prevalent cardiac complications observed in COVID-19 patients (from 20 to 45% of the patients). Acute cardiac injury was found to be an independent risk factor for severe forms of SARS-CoV-2 infection and an independent predictor of mortality.
In the international survey by Dweck et al., the author observed echocardiographic evidence of Takotsubo syndrome (TTS) in 2% of cases (19 patients), associated with an increase in troponins (10 patients) and BNP levels (5 patients) [24]. Similarly, Stöbe et al. performed an echocardiographic evaluation study on COVID-19 patients in order to characterize the cardiac abnormalities in this group of patients [63]. Interestingly, the authors performed myocardial deformation analysis, with the evaluation of global and regional circumferential and radial layer strain deformation. They found that the cardiac abnormalities were high in the COVID-19 patients included. The most common findings were a reduced longitudinal strain (71%), absence or dispersion of basal rotation (43%), and reduced circumferential strain in the mid and basal segments (50%). The authors concluded that in the majority of the patients included the LV dysfunction observed was similar to "reverse basal Takotsubo like syndrome." Takotsubo was also described in three case reports [34,40,45]. In both cases, chest discomfort, elevation of troponin, and EKG alterations were observed with negative coronary angiography. Similarly, the woman was treated with medical therapy and was discharged at home after the resolution of echocardiographic abnormalities. In the clinical cases described by the Spanish and the Italian group, the authors observed an inverted TTS: akinesia of the basal segments of the left ventricle on echocardiographic evaluation [40,45].
In the international survey of Dweck et al., the authors observed 35 cases of myocarditis (3% of the population studied) with an associated increase in troponin (19 patients) and BNP levels (13 patients) [24]. In the retrospective study by Deng et al., 14 cases (12.5%) of suspected myocarditis were observed [19]. The authors followed the statement from the American Heart Association for the diagnosis of myocarditis [66]. The patients with suspected myocarditis presented the following clinical characteristic: -A mean age of 74 years -Predominantly men (71.4%) -Comorbidities: hypertension (42.6%), diabetes (28.6%), and coronary artery disease (21.4%) Fourteen patients presented an increase in cardiac biomarkers (i.e., CK-MB and pro-BNP). Even more, 10 patients presented alteration in echocardiographic evaluation, 2 in EKG, and 2 in both exams. In comparison with 98 patients without suspected myocarditis, the authors observed a statistical difference for age, blood saturation of oxygen shortness of breath, and respiratory rate at admission.
In the retrospective study of Kunal et al., the authors enrolled 108 patients with COVID-19 [32]. Myocarditis was classified based on the level of diagnostic certainty: -Histological/immunohistological evidence -Symptoms/ECG findings/cardiac biomarkers/TTE/ cardiac MRI However, no proven data on intra-myocytes active viral replication were found.

Pericardial effusion
Pericardial effusion was evaluated in five of the papers retrieved (as shown in Table 5): one international survey [24], three retrospective studies [16,19,32], and one case report [18]. All the aforementioned studies aimed at analyzing cardiac complications in patients with COVID-19 patients.
In the prospective international study by Dweck et al., cardiac tamponade represented the indication for performing echocardiographic evaluation in 2% of the cases (20 patients) [24]. Cardiac tamponade was confirmed in 1% of the cases.
In the retrospective study by Chen et al., echocardiographic evaluation was performed in 31 patients; pericardial effusion was observed in 5 critical patients and 1 severe case (P < 0.01). Pericardial effusion was found to be an independent risk factor predicting the critical status of COVID-19 patients (OR = 3.5, 95% CI 1.8-15.1, P = 0.5) [16]. Kunal et al. reported two cases of pericardial effusion (1.9%): one patient with moderate pleural effusion without cardiac tamponade [32]. In the study by Deng et al., pericardial effusion > 5 mm was observed in 19.6% (22 patients) with a statistically significant difference in the percentage of PE in patients with severe versus non-severe form of COVID pneumonia (28.3 vs. 6.7%, P < 0.01) [19]. In 13.4% of patients, the authors also observed signs of pulmonary hypertension (according to the definition of the American Society of Echocardiography and the European Society of Cardiology) [67,68].
In the prospective international study by Dweck et al., ventricular arrhythmia represented the indication for performing echocardiographic evaluation in 3% of the cases (38 patients); 33 of 38 patients presented echocardiographic alterations [24]. Contrarily, Yu et al. observed 9.3% of arrhythmic complications (21patients) mostly represented by atrial fibrillation (%) [54]. Supraventricular tachycardia was observed in 2 patients whereas ventricular tachycardia was found in one patient. In the retrospective study by Chen et al., the authors described several ECG alterations and compared the percentage between severe and critical patients [16]: -Sinus tachycardia 59% (23 patients) of severe patients versus 100% of the critical group (P < 0.1) -Ventricular tachycardia 13.3% (2 patients) of severe patients versus 2.6% (1) of the critical group (no statistical difference) -Premature beat 20.5% (8 patients) of severe patients versus 13.3% (2 patients) of the critical group (no statistical difference) -Atrioventricular block 0% of severe patients versus 13.3% (2 patients) of the critical group (P = 0.2) -Sinus bradycardia 5.1% (2 patients) of severe patients versus 6.7% (1 patient) of the critical group (no statistical difference) -Atrial fibrillation 0% of severe patients versus 6.7% (1 patient) of the critical group (no statistical difference) Remarkably, the authors stressed that they did not observe an association between tachycardia and body temperature or oxygen saturation.
Tachycardia was observed in 29.5 % of the cases (33 patients) in the retrospective study by Deng et al. [19]: no statistical difference was observed between severe versus non-severe forms of COVID pneumonia (P = 0.34). Zhang et al. reported 22 cases of arrhythmia complications in the severe form of COVID-19 patients (40% vs. 1.2%, P < 0.001) [56]. Du et al. reported 60% of arrhythmic complications; in 2.47% of cases, malignant arrhythmia represented the cause of death [22]. Cao et al. found arrhythmic complications in 38.9% of intensive care patients in comparison to 13.1% of nonintensive patients [15]. Guo et al. reported an incidence rate of 7% for VT and VF [25].
In the retrospective case series of Amaratunga et al., the authors highlighted bradycardia as a possible important complication of COVID viral infection [11]. Even more, they suggested that the onset of bradycardia in COVID patients has to be regarded as a possible manifestation of a serious cytokine storm. These patients required closer monitoring for possible cardiological sequelae. The authors also speculated on possible etiologists: hypoxia, inflammatory cytokine storm, and drug integrations. Remarkably, the four cases described presented sinus bradycardia, not associated with high changes in temperature: three out of the four patients were sedated with propofol or dexmedetomidine, but the bradycardia persisted even when the same drugs were discontinued. An important aspect to analyze was the association between bradycardia and hypotension; three patients required the use of vasopressors in order to maintain PAM > 65 mmHg.
In the retrospective study by Chen et al., echocardiographic evaluation was performed in 31 patients. Right ventricular dysfunction, with right heart enlargement/ pulmonary hypertension, was observed in 2 critical patients, care; both patients died [16].
Comparing patients with severe and mild symptoms, St be et al. did not find a statistically significant difference in RV function [63]: global longitudinal strain (GLS) of the free wall was −26.6 ± 5.9% in severe cases vs. −27.5 ± 6.1 % in mild cases (P = 0.76). In four out of ten patients with severe symptoms, RV GLS was mildly reduced (between −17 and −23%), with a higher value of troponin T and NT-pro-BNP. Similarly, in two out of four patients with mild symptoms, RV GLS was mildly reduced (between −22 and −23%).
Szekely et al. evaluated right ventricular function analyzing RV fractional area change, tricuspid annular plane systolic excursion, systolic lateral annular velocity, and pulmonic flow acceleration time (AT) velocity [47]. RV dilation was found in 39% of the patients and represented the most common echocardiographic pattern in COVID-19 patients. Increased RV end-diastolic area was significantly associated with mortality (1.14 [HR, 1.01-1.32]; P = 0.05 for 1 cm 2 ).

Risk factors
The following risk factors were highlighted during the literature search: Hypertension: the majority of the article reported hypertension as one of the main risk factors in patients with COVID-19. Hypertension was observed in 55.6% of the COVID-19 included in the study of Shao et al. [42]. Cao et al. observed that ICU patients were more probable to suffer from comorbidities and found hypertension in 55% of the cases [15]. Chen et al. found that hypertension was more frequent in deceased patients in comparison to recovered (48% vs.24%) [17]. In the study of Zhang et al., hypertension was observed in 24.4% of the patients included, with a significant difference between   [12]. Inversely, Deng et al. found chronic obstructive pulmonary disease in 13.4% of the cases; no statistically significant difference was found between severe and non-severe forms (P = 0.53) [19]. Shi et al. did not find a significant difference for chronic obstructive pulmonary disease in the group of non-survivors in comparison with the survivor group (P = 1.0) [44].
Due to the few cases included, it is difficult to draw any conclusion to the real impact of malignancy chronic kidney disease, chronic liver disease as risk factors on COVID-19 [17,22,23,25,27,32,44,52,54,[56][57][58]63]. In one study, chronic kidney failure represented the most common comorbidities among COVID-19 patients (47.6%) [12]. Cancer was statistically significantly different in patients with cardiac injury in comparison with patients with no cardiac injury in the study of Shi et al. [43].

Discussion
Emerging evidence showed that, besides acute respiratory disease, cardiac complications may also occur in COVID-19 patients with a severe impact on outcome [8]. Consequently, it is extremely important to further evaluate and share awareness regarding the correlation between COVID-19 and cardiovascular implications.
In our systematic review, we observed that the rate of patients suffering from an acute cardiac injury or myocardial infarction varied among the studies. This can be explained partially by the heterogeneity of the studies included. However, ACI represented the predominant cardiac complications in COVID-19 patients in several studies included (from 20 to 45% of the patients). Patients with acute cardiac injury seemed to be significantly older and with comorbidities. Patients with cardiac injury were more likely to develop complications during the hospital stay with higher mortality rates. ACI was found to be an independent risk factor for the severity of SARS-CoV-2 infection and an independent predictor of mortality. In our meta-analysis, we found a statistically significant difference between non-survivor and survivor in patients with acute cardiac injury (P < 0.0001; I 2 = 80%). Myocardial infarction, heart failure, and cardiogenic shock were also described in the literature, with a smaller incidence among COVID-19 patients. Due to the paucity of prospective studies with data mainly basing on case reports, it was not possible to draw any conclusion regarding Takotsubo, myocarditis, and pericardial effusion. Remarkably, the incidence rate of arrhythmia events during hospitalization varied widely among the studies (from 3 to 60%). This can be explained by the wide difference of inclusion criteria between the studies. Several ECG alterations were described (i.e., sinus tachycardia, ventricular tachycardia, premature beat, sinus bradycardia, atrial fibrillation) at different stages of disease. The presence of arrhythmia should be evaluated also in the context of hypoxemia degree and in relation to cardiac, metabolic, and multiorgan deterioration. Analyzing the studies retrieved, it was not possible to draw any assumption regarding the possible association between arrhythmia and comorbidities. Hypertension seemed to represent the most common comorbidities in COVID-19 patients (from 30 to 59.8%); however, the evidence regarding the relation between hypertension and severity of the disease and mortality was inconclusive. The prevalence of cardiovascular disease was high in this group of patients (up to 57%); in particular, coronary artery disease seemed to be around 10% of the cases. In the majority of the studies retrieved, patients with CVD had a higher prevalence of severe form, ICU admission, and higher mortality rates. Furthermore, diabetes emerged as an important risk factor in COVID-19 patients although the evidence is scarce. Due to the lack and the heterogeneity of the cases included, it was not possible to draw conclusions regarding the real role of cerebrovascular disease, chronic respiratory diseases, malignancy, chronic kidney disease, and chronic liver disease as risk factors on COVID-19.
Several physio-pathological mechanisms were proposed to explain the cardiovascular manifestations in COVID-19 patients (i.e., direct and indirect mechanisms): etiology is characterized by a complex interaction between virus, host responses, and underlining cardiac comorbidities [9]. Even if patients with several The authors described acute myocardial infarction as "acute myocardial injury with clinical evidence of acute myocardial ischemia." Consequently, for the diagnosis of acute myocardial infarction, there is a need to observe, on top of ACI, at least one of the following symptoms of myocardial ischemia: ECG changes, development of Q waves, documentation of coronary thrombus, and TTE abnormalities [73]. However, the widespread use of a homogeneous and standardized definition allows comparison and trend analysis between studies over the time. The importance of a clear and internationally approved definition should be also stressed for myocarditis [83]. Approximately half of the studies retrieved used cardiac magnetic resonance evaluation to reach a diagnosis of myocarditis. However, only three articles referred to specific international guidelines/recommendations for the diagnosis of myocarditis.
Second, the long-term consequences of cardiac manifestations in COVID-19 patients remain basically uncertain due to the limited period of time for post-trial follow-up. A relatively short follow-up period may fail to evaluate the real impact of cardiac complications on outcome. However, follow-up represented a limitation to take into account. Third, we included several case reports and case series. Besides the debatable role of case reports in the era of evidence-based medicine, case reports present several interesting aspects not to be underestimated especially in the COVID-19 pandemic period. Case reports can have an important impact on clinical practice. Case reports can allow a rapid identification of a new disease or complications, consequently can represent an important warning signal, and can promote communication between the medical community. Observation to publication time is short, and this can lead to rapid detection of unusual or harmful clinical findings or complications. As a consequence, case reports can change clinical practice and stimulate the design of further studies. Nevertheless, there is a huge need of welldesigned observational studies. Few studies were focused on a specific cardiac complication. Indeed, in order to reach evidence, it is vital to perform large well-designed observational studies aiming to investigate a specific aspect of cardiac complications, following clear and wellstandardized definitions.

Conclusions
Acute cardiac injury represented the prevalent cardiac complications in COVID-19 patients. Patients with acute cardiac injury appeared to be significantly older, with comorbidities, more prone to present complications, and with greater mortality rates. Arrhythmic complications have to be carefully considered by physicians in COVID-19 patients for the possible consequences and complications. Even if inconclusive, it seemed that the presence of coexisting medical conditions is prominent in COVID-19 patients. Few studies were focused on a specific type of cardiac complications. Indeed, in order to reach evidence, it is vital to perform large well-designed observational studies aiming to examine the prevalence of specific cardiac complications, following clear and well-standardized definitions.